Highlights from Recent Cancer Literature
Journal: Cancer Research (2012)

Serres MP, Kossatz U, Chi Y, Roberts JM, Malek NP, Besson A. p27Kip1 controls cytokinesis via the regulation of citron kinase activation. J Clin Invest 2012;122:844–58.The well-known tumor suppressor p27Kip1 inhibits cell proliferation by blocking cyclin-dependent kinase (CDK) activity. However, p27 also has CDK inhibitor–independent roles, such as preventing activation of the GTPase RhoA to modulate cell migration. Recent publications support an oncogenic role for p27. In these studies, mice expressing a form of p27 (p27CK−) that cannot bind to the CDK complex display increased tumor formation. Serres and colleagues identified a mechanism by which this mutant form of p27, at least in part, contributes to tumor initiation. They observed multinucleated cells in the liver and in primary fibroblast cultures derived from p27CK− mice. Through video-microscopy analysis, they showed that p27CK− cells harbor cytokinesis defects. At the molecular level, Serres and colleagues discovered that p27 and p27CK− interact with the Rho effector citron kinase (citron-K). Furthermore, p27 and citron-K colocalize at the contracting ring of the midbody during cytokinesis. The authors present a series of findings suggesting that p27CK− causes multinucleation by interfering with citron-K function, specifically through a mechanism by which p27CK− competes with Rho GTPases for binding to citron-K. This new role for p27 in cytokinesis may explain, at least in part, the tumor-prone phenotype of p27CK− mice. The relevance of these data is highlighted by the fact that p27 is a tumor suppressor that is rarely mutated in human cancer; rather, its expression or localization is found altered. Furthermore, some human tumors with normal levels of p27 expression nevertheless show mislocalization of p27 in the cytoplasm. Interestingly, increases in the cytoplasmic mislocalization of p27 are positively associated with increasing tumor aggressiveness. It would be important to assess whether p27 can contribute to human cancer by altering cytokinesis and inducing polyploidy when mislocalized.Malanchi I, Santamaria-Martínez A, Susanto E, Peng H, Lehr HA, Delaloye JF, et al. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 2012;481:85–9.Factors governing metastatic colonization of infiltrating tumor cells remain largely unidentified. Using the MMTV–PyMT mouse breast cancer model, Malanchi and colleagues recently discovered that the stromal factor Postn, which encodes a component of the cellular matrix known as periostin, is required for the initiation and maintenance of both normal stem cell niches and the metastatic niche. Moreover, the authors showed that a small population of breast cancer stem cells (CD90+ CD24+) is critical for metastatic colonization to the lung. The initial expansion of these cancer cells to this secondary site requires the induction of Postn in lung stroma. Interestingly, stromal expression of Postn increased Wnt signaling specifically in cancer stem cells by recruiting Wnt ligands. Deleting and/or blocking Postn expression prevented metastases to the lung without affecting normal mammary gland development or tumor formation at the primary site. Together, these findings indicate that breast cancer stem cells require the induction of niche signal, such as Postn, at the secondary site to initiate and promote metastatic colonization. Targeting inhibitors of niche factors, such as Postn, may therefore offer attractive therapeutic potential for treatment and prevention of metastatic disease.Leung CK, Brugge JS. Overgrowth of single oncogene-expressing cells from suppressive epithelial environments. Nature 2012;482:410–3.In this exciting article, Leung and Brugge investigate the early cellular events by which cells harboring a single oncogene surrounded by normal tissue initiate clonal expansion from a well-organized epithelial layer. They used 3-dimensional (3D) organotopic cultures, which exhibit many of the characteristics of cell organization found in epithelial tissue. Nontransformed normal human epithelial cell line MCF10A cells can be cultured into a structure that recapitulates mammary acini, wherein a single layer of polarized cells surrounds a lumen. The authors induced expression of distinct oncogenes in single cells of the MCF10A-derived acini and found that only ERBB2, a receptor tyrosine kinase found amplified in many human breast tumors, specifically triggers cell translocation from the epithelial layer to the lumen as well as luminal outgrowth. Leung and Brugge further show that the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway is important for ERBB2 single-cell translocation in this 3D culture. They mechanistically show that ETS1, a transcription factor regulated by ERK activity, drives cell translocation to the lumen, presumably by activating proteinases, such as matrix metalloproteinase. Interestingly, ERBB2-mediated single-cell translocation is also dependent on local cell matrix adhesion. Indeed, the results of this study suggest that epithelial organization mediated by the p120-catenin junction is essential for suppressing oncogene-induced proliferation in epithelial acini. Whether the cells undergo outgrowth and perhaps form a tumor depends on the nature of the oncogenic lesion. In fact, in the context of this article, the authors show that translocated Myc-overexpressing cells undergo induced programmed cell death, whereas those overexpressing an active form of AKT have a survival advantage. These data collectively support a model by which the specific cellular and molecular events leading to outgrowth of single cells in a very well-organized epithelial tissue structure depend on the earliest oncogenic lesions, which will favor cancer clonal selection in vivo for tumor initiation.Wu X, Northcott PA, Dubuc A, Dupuy AJ, Shih DJ, Witt H, et al. Clonal selection drives genetic divergence of metastatic medulloblastoma. Nature 2012;482:529–33.Medulloblastoma is the most common malignancy of childhood. Dissemination of tumor cells within the cerebrospinal fluid does not necessarily require that cells traverse across a basement membrane, but nevertheless shares many features with hematogenous or lymphatic metastasis. Cells that detach from the primary tumors must survive while circulating in the cerebrospinal fluid, and then must reestablish tumors at a distant site. As with other forms of metastasis, dissemination of medulloblastoma is also associated with poor prognosis. To understand the genetics of dissemination in medulloblastoma, Wu and colleagues drove metastasis in 2 distinct genetically engineered mouse models of medulloblastoma, using a forward genetics approach (transposition of Sleeping Beauty). They then compared insertions in primary tumors and in metastases and paired these data with analyses of matched human primary and metastatic medulloblastoma. These studies showed that multiple metastases from a single mouse or human patient were very similar to one another but diverged from the matched primary tumor. Only rare cells within the primary tumor were able to metastasize, as clonal genetic events in the metastases were limited to restricted subclones within the primary tumor. These data suggest that medulloblastoma is a bicompartmental disease, and that distinct therapeutic approaches are required to target metastatic tumors as compared with primary medulloblastoma tumors.Noguchi T, Kato T, Wang L, Maeda Y, Ikeda H, Sato E, et al. Intracellular tumor-associated antigens represent effective targets for passive immunotherapy. Cancer Res; Published OnlineFirst February 8, 2012; doi:10.1158/0008-5472.CAN-11-3072.Monoclonal antibody (mAb)–based immunotherapy has been found to be beneficial for treatment of various cancers in clinical settings. However, a major restriction of this approach relates to intracellular antigens, which are generally not considered to be suitable targets for this type of therapy. To overcome this hurdle, Noguchi and colleagues used a combination of anti-NY-ESO-1 mAb, a frequently expressed intracellular cancer testis antigen discovered through serologic identification of antigens by recombinant expression cloning (SEREX) using serum from a patient with esophageal cancer, along with various anticancer drugs. Combinatorial treatment with NY-ESO-1 and 5-fluorouracil (5-FU) in particular resulted in the release of intracellular NY-ESO-1 from shedding CT26 colon tumor cells overexpressing NY-ESO-1 (CT26-NY-ESO-1 in BALB/c mice). This, in turn, resulted not only in the generation of antigen-specific antibody but also in antigen-specific CD8+T/CD4+ response and tumor growth inhibition. Additionally, augmentation of dendritic cells was observed following treatment. Furthermore, it has been shown that the Ab/Fc portion was required for the augmented antitumor effect. In these contexts, development of combinatorial treatment strategies targeting intracellular antigens, such as NY-ESO-1, which is expressed in cancer cells of various tissue origins but not in normal somatic cells except for germ cells in the testis, along with specific chemotherapeutic agents, is a potentially viable approach for developing immune responses to intracellular antigens. An enhanced understanding of the precise molecular mechanism(s) underlying this combinatorial approach could be very useful for developing improved immunologic approaches in the future for treating different cancers.Kohrt HE, Houot R, Weiskopf K, Goldstein MJ, Scheeren F, Czerwinski D, et al. Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J Clin Invest 2012;122:1066–75.Many people believe that the most effective way to use targeted cancer therapies is to combine them in a rational fashion. Kohrt and colleagues describe a sequential antibody treatment strategy involving a tumor-targeting antibody and one that activates the host immune system. Trastuzumab is a humanized monoclonal antibody used to treat the 25% of breast cancer patients whose tumors overexpress HER2, but response rates in metastatic disease to anti-HER2 monotherapy are only 10% to 15%. Antibody-dependent cellular cytotoxicity is a major mechanism of action of trastuzumab and requires immune cells, mainly NK cells, to bind to the antibody-clad tumor cells via their Fc receptors. Therefore, a therapy that would increase the cancer-killing activity of NK cells may well improve the efficacy of trastuzumab. Because the costimulatory molecule CD137 is upregulated on NK cells when they encounter antibody bound to malignant cells, these authors tested a combination of a CD137 agonist antibody and trastuzumab on human cells in vitro and in breast cancer xenografts in nude mice (which still have NK cells). Studies in patients receiving trastuzumab confirmed that CD137 expression increased on NK cells by approximately 2-fold after 24 hours. These results clearly show that sequential use of the 2 antibodies was more effective, with the cancer cells being first treated with trastuzumab and then the NK cells further activated with the CD137 agonist. This sequential antibody approach may also enhance the activity of other therapeutic antibodies, such as rituximab and cetuximab, which bind to malignant cells. It will be interesting to see if these data translate positively to clinical trial without any untoward side effects.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.